N-alkinyl and n-alkinyloxy-amides of 4-phenyl - 1,2,5,6 - tetrahydropyridino alkanoic acids and intermediates thereof



United States Patent C) N-ALKINYL AND N-ALKINYLOXY-AMIDES F 4- PHENYL1,2,5,6 TETRAHYDROPYRHDINO AL- KANOIC ACIDS AND INTERMEDIATES THERE- 0FJohn H. Biel and Harvey B. Hopps, Milwaukee, Wis., as-

signors to Aldrich Chemical Company, Inc., Milwaukee, Wis, a corporationof Wisconsin No Drawing. Filed Apr. 7, 1964, Ser. No. 358,115

12 Claims. (Cl. 260-295) This invention relates to novel4-arylpyridines. More particularly, this invention relates to N-alkinyland N- alkinyloxy amides of 4-phenyl-1,2,5,6-tetrahydropyridino alkanoicacids and a process for the preparation thereof. In a further aspect,this invention relates to novel intermediates useful in processes forpreparing the novel 4- arylpyridines of this invention. I

In accordance with the present invention, there is provided a memberselected from the group consisting of 4-arylpyridines of the formula Rand R are each a member selected from the group consisting of hydrogen,chloro, bromo, iodo, fluoro, trifiuoromethyl, amino, nitro,(lower)alkyl, (lower) alkoxy, hydroxy, phenyl, phenoxy, benzyl,(lower)alkylamino, di (lower)alkylamino, (lower)alkanoylamino,(lower)alkylthio, sulfamyl, (lower)alkanoyl, (lower) alkylsulfonyl,methylenedioxy, cycloalkyl radicals having from to 7 carbon atomsinclusive and cycloalkoxy radicals having from 5 to 7 carbon atomsinclusive;

W is a member selected from the group consisting of oxy(lower)alkyleneand (lower)alkylene radicals;

Y is a (lower)alkylene radical;

Z and Z are each a member selected from the group consisting ofhydrogen, (lower)alkyl, and radicals of the formulae C nHzn) and (III) RR wherein n is a whole integer from 0 to 6 inclusive, and

R and R are each a member selected from the group consisting ofhydrogen, chloro, bromo, iodo, fiuoro, trifluoromethyl, amino, nitro,(lower)alkyl, (lower) ice alkoxy, hydroxy, phenyl, phenoxy, benzyl,(lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino,(lower)alkylthio, sulfamyl, (lower)alkanoylamino, (lower)alkyltl1io,sulfamyl, (lower) alkanoyl, (lower) alkylsulfonyl, methylenedioxy,cycloalkyl radicals having from 5 to 7 carbon atoms inclusive andcycloalkoxy radicals having from 5 to 7 carbon atoms inelusive;

and the pharmateutically acceptable nontoxic salts thereof.

Among the radicals represented by R R R and R hydrogen, chloro, bromo,iodo, fluoro, trifluoromethyl, nitro, (lower)alkyl, (lower)alkoxy,(lower)alkylthio, (lower)alkanoyl, phenyl, phenoxy and benzyl arepreferred; preferably R or R and R or R are hydrogen and usually R R Rand R are all hydrogen. W is preferably methylene and Z is preferablyhydrogen.

The pharmaceutically acceptable nontoxic salts include the organic andinorganic acid addition salts, e.g. those prepared from acids such ashydrochloric, sulfuric, sulfarnic, tartaric, funiaric, hydrobromic,hydriodic, glycolic, citric, maleic, phosphoric, succinic, acetic andthe like.

The term (lower)alkyl as used herein means both straight and branchedchain aliphatic hydrocarbon radicals having from 1 to 8 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, hexyl, 2-ethylhexyl, etc.

Similarly, where the term (lower) is used as part of the description ofanother group, e.g. (lower)alkoxy, it refers to the alkyl portion ofsuch group which is therefore as described in connection with(lower)alkyl.

The meaning of the term (lower) alkylene is similar to that of(lower)alkyl in that it also means both straight and branched chainaliphatic hydrocarbon radicals having from 1 to 8 carbon atoms. Examplesof (lower)alkylene radicals are methylene, ethylene, propylene,isopropylene, butylene, isobutylene, t-butylene, amylene, hexylene,2-et-hylhexylene and the like.

The compounds of this invention are valuable pharmaceutical agents. Theyproduce pain relief which makes the compounds useful as analgesicagents. In addition, the compounds, being tertiary bases, can be used torecover and purify penicillin with which they form salts.

The 4-arylpyridines of the present invention were tested for analgesicactivity by the phenylquinone test of Sigmund et al., Proc. Soc. Exptl.Biol. and Med., 95, 729 (1957) in which an analgesic reduces the inducedwrithing of the mice. The compounds were administered at dosages of 150mgm./kg. p.o. in mice, 50 minutes before the phenyl-p-quinone wasinjected. The reduction in induced writhing was determined at the end ofthe first hour. When, for example, N-benzyl-N-2-propinyl-,B(4-phenyl-l,2,5,6-tetra-hydropyridino) propionamide fumarate was tested,the reduction in induced writhing at the end of the first hour was foundto be 67% for the compound compared to for aspirin. This indicated thatN benzyl N-2-propinyl-8-(4-phenyl-l,2,5,6-tetrahydropyridino)propionamide fumarate is ananalgesic agent with a potency of the order of that of aspirin.

The compounds of the present invention are prepared by the followingseries of steps:

(1) An alkinyl or alkinyloxyamine of the formula wherein W, Z and Z areas represented above, is reacted with an equimolar quantity of a haloortosyl acid chloride of the formula AYi )-Cl wherein A is a radicalselected from the group consisting of chloro, bromo, iodo or tosyl, andY is as represented above according to the method described in US.Patent No. 2,569,288 and by A. Marszak-Fleury, Ann. Chim. (Paris), [13]3:656 (1958); CA. 54:3178i (1960).

wherein A, W, Y, Z and Z are as previously defined. The product, anN-alkinyl or alkinyloxy haloor tosylalkanoic acid amide, is a novelintermediate, useful in the second step of the method for thepreparation of the 4-aryl-l,2,5,6-tetrahydropyridines of Formula I, andis considered within the scope of this invention.

(2) The N-alkinyl or alkinyloxy haloor tosylalkanoic acid amide preparedin Step 1 or a quaternary ammonium salt of the compound, (e.g. CHCH CHNI) is then reacted with an equimolar quantity of a1,2,5,6-tetrahydropyridine of the formula wherein R and R are asdescribed above, in the presence of triethylamine and dimethylformamide,and a trace of potassium iodide at elevated temperature, i.e., 65-70 C.,for several hours according to the procedure described in United StatesPatent No. 2,929,818. The cooled reaction mixture is then poured intoWater containing an equirnolar amount of sodium hydroxide. The free baseis collected by filtration and dried.

wherein A, R R W, Y, Z and Z are as defined above. The free base may bereadily converted, if desired, to a nontoxic acid addition salt byconventional procedures.

An alternate procedure for preparing the compounds of the inventioncomprises the addition of the secondary piperidine to an acrylic acidamide or a substituted acid amide in the presence of a strong base,e.g., sodium hydroxide, according to the equation wherein A, R R W, Y, Zand Z are as described above, and- R is methyl, ethyl, p-nitrophenyl,cyanomethyl, succinimido, phthalimido, and OR may also be, chloro orbromo.

In each of the three mehods for the preparation of the compounds of thisinvention, the secondary piperidine and other reactants are broughttogether in a suitable medium such as dimethylformamide, ethanol,isopropyl alcohol, toluene, xylene, dimethoxyethane, diethyleneglycol,and heated at 50-100 C., for several hours in the presence of a basesuch as triethylamine, aminopyrine, diethylaniline, potassium carbonateand triethyl phenyl ammonium hydroxide. The cooled reaction mixture isthen poured into dilute sodium hydroxide. The basic amide or esterprecipitates either as a water-insoluble oil or a crystalline solid, andis extracted with such solvents as methylene dichloride, chloroform,carbon tetrachloride, or by filtration of the solid product. In the caseof the third process, the ester that is obtained, is reacted withpropinylamine, or a substituted propinylamine; the product is thenconverted to a nontoxic acid addition salt.

It is obvious that in some cases, the radicals attached to the aromaticring, e.g., the amino radical, will interfere with the reactions used inpreparing the compounds of this invention. Therefore, it is necessary toblock the reactive radicals before proceeding with the reactions. Thisis conveniently accomplished by methods known in the art. For example,in the case of an amino substituted aromatic ring, the amino group isblocked by forming the Schitfs base by reacting the aromatic amine withan aldehyde such as acetaldehyde, and after all reactions have beencompleted, the Schiifs base may be cleaved with dilute hydrochloric acidto regenerate the free amino group.

The starting materials necessary for the processes described herein arecompounds which are either commercially available, well known in theprior art, or easily prepared in accordance With standard organicprocedures preciously described. in the chemical literature. Forexample, one method for preparing propargyloxyamine is described inBritish Patent No. 889,086. Another convenient method for preparingpropargyloxyamine consists of first reacting hydroxylphthalimide withpropargyl bromide in the presence of potassium carbonate and a solventsuch as dimethylformamide to produce N-propargyloxyphthalimide and thenreacting the N-propargyloxyphthalimide with acetic acid in the presenceof concentrated hydrochloric acid to form propargyloxyamine. Thepreparation of propargylamines are described by A. Marszak-Fleury, Ann.Chim. (Paris) [13] 3:656 (1958); CA. 54:3178i (1960).

The compounds of this invention may be administered as the free bases orin the form of their nontoxic addition salts. They may be compounded andformulated into pharmaceutical preparations for oral or parenteraladministration with organic or inorganic solid materials or liquidswhich are pharmaceutically acceptable carriers. The compositions maytake the form of tablets, powder granules, capsules, suspensions,solutions and the like. Such compositions are considered within thescope of this invention.

The following examples are intended to illustrate the inventiondescribed herein without unduly limiting it.

EXAMPLE 1 Preparation of propargyloxyamine A mixture ofhydroxylphthalimide (40.5 gm.), propargyl bromide (120 gm.), potassiumcarbonate (18 gm.), and dimethylformamide (15 gm.), is refluxed for 24hours. After cooling, N-propargyloxyphthalimide crystallizes from themixture. After adding 30 ml. of ethanol, the mixture is filtered withsuction, washed with ethanol, and then ground in a mortar with water. Itis filtered again, and Washed with water until free of bromine, washedagain with ethanol and air-dried. Crude N-propargyloxyphthalimide isobtained which is found to weigh 31 gm. and have a melting point of146149 C. Pure N-propargyloxyphthalimide is obtained byrecrystallization from ethanol and has a melting point of 149- 150 C.,and the following analysis:

Analysis.Ca lcd for C I-I NO C, 65.67%; H, 3.51%; N, 6.96%. Found: C,65.30%; H, 3.62%; N, 7.03%.

A mixture of propargyloxyphthalimide (30 gm.), glacial acetic acid (125ml.), and concentrated hydrochloric acid (35 ml.), is heated withstirring, and refluxed for 0.25 hour. Rapid solution occurs. Aftercooling, the mixture is neutralized with concentrated sodium hydroxidesolution to pH 8.0. Then the solution is extracted with methylenechloride and a salt of propargyloxyamine is precipitated by treatingwith hydrogen chloride; and weighs 7.5 gm. and has a melting point of156-158 C. The salt is dissolved in n-butanol (60 ml.) at 60 C., 20 ml.of ether are added, and the mixture cooled very slowly, finally, in arefrigerator. Propargyloxyamine is obtained, weighing 5 gm., and havinga melting point of 160161 C. The structure is confirmed by infraredanalysis.

EXAMPLE 2 Preparation. of N-propargyloxy-B-chloropropionamide To astirred solution of fl-chloropropionyl chloride (105 gm., 0.826 mole)and benzene (1 liter), cooled to 5 C., is added a solution containingpropargyloxyamine (58.8 gm.; 0.826 mole) and triethylamine (83.5 gm.;0.826 mole) during a period of two hours. The reaction mixture isclarified by filtration, washed with dilute sodium hydroxide followed bya dilute acid wash and the benzene solution concentrated in vacuo. Theresidue crystallizes on standing and the solid product is collected byfiltration. Recrystallization from benzene-heptane yields 35 gm. ofN-propargyloxy-B-chloropropionamide having a melting point of 86-87.5 C.

EXAMPLE 3 Preparation of N-propargyl-fl-chloropropionamide To a stirredsolution of fi-chloropropionyl chloride (0.826 mole) and benzene (1liter), cooled to 5 C., is added a solution containing propargylamine(0.826 mole) and triethylamine (83.5 gm.; 0.826 mole) during a period oftwo hours. The reaction mixture is clarified by filtration, washed withdilute sodium hydroxide followed by a dilute acid wash and the benzenesolution concentrated in vacuo. The residue crystallizes on standing andthe solid product is collected by filtration. Recrystallization frombenzene-heptane yields N-propargyl-fi-chloropropionamide.

EXAMPLE 4 Preparation of N-benzyl N-propargyl-jS-chloropropionamide To astirred solution of B-chloropropionyl chloride (12.7 gm.; 0.1 mole)dissolved in 60 ml. of benzene, cooled to 0 C., is added a solutioncontaining N-benzyl- N-propargylamine (14.5 gm.; 0.1 mole),triethylamine (10.1 gm.; 0.1 mole), and benzene (60 ml.). The rate ofaddition is adjusted to keep the reaction below 10 C. The mixture isstirred for two hours at 10 C. and then permitted to warm to roomtemperature overnight. The insoluble precipitate is removed byfiltration and washed with approximately 200 m1. of hot benzene. Thecombined filtrate and washings are dried over potassium carbonate. Thebenzene solution is concentrated to produce 13.4 gm. ofN-benzyl-N-propargyl-B-chloropropionamide.

EXAMPLE 5 When equivalent quantities of the appropriate startingmaterials are substituted in the above procedures, the followingcompounds are obtained N- (2-propinyl) -,8-bromopropionamide,N-(2-propiny1)w-bromopropionamide,

N- (2-propinyl) -N-b enzyl-B-bromobutyramide,

N- (Z-butinyl -a-methyl-fl-chloropropionamide,

N( l-methyl-Z-propinyl) -'y-hromobutyrarnide,

N- 1, 1-dimethy1-2-propinyl)-}8-chloropropionamide,

N.( Z-propinyl -l3-chlor0acetamide,

N- 2rpropinyl) -,8-iodopropionamide,

N- (2-propinyl -'y-c-hlorohexanoamide,

N( 2-propinyl -p-tosylpropionamide,

N- 2-propinyl -a-Cl'1l0f0 propionamide,

N- (2-propinyl -N-methylfihhloropropionamide,

N- Z-propinyl -N-propyl-fi-chloropropionamide,

N- 2- pro pinyl -N-phenyl-flchloroprop-ionamide,

N( 2-propinyl) -N-(4-trifiuoromethylphenyl 3-chloropropionamide,

N- 2-propinyl -N- l-naphthyl -,B-chloroprpionamide,

N-(2-propinyl -N- l-methyl-Z-naphthyl -[3-chloropro-pi-onamide,

N- 3-phenyl-2-propinyl -,B-chloropropionamide,

N- 3-ethyl-2-propinyl -fl-chloropropionamide,

N 3-is opropyl-Z-propinyl fi-ohloropropiona mide,

N- 3-*benzyl2-propinyl -[3-chloropropionamide,

N- 3 l-naphthyl-Z-propinyl) -fl-ehlonopropionamide N- 3-2-naplrthyl-2-propinyl -fl-chloropropi0-namide,

N- 3-1-naphthylmethyl-Z-propinyl) -fi-chloropropionamide,

N- 3-4-ch1orophenyl-Z-propinyl e-chloropropionamide,

N- 3-4-tnifiuoromethylphenyl-Z-propinyl) e-chloropropionarnide,

N- 3-4-methylphenyl-2-propinyl -fl-chloropropionamide,

N 3-2-fluorophenyl-Z-propinyl -[3-chloro-propionamide,

N- 3-3-methylphenyl-2propinyl -fl-chloropropionamide,

N- 3-3 -'bromophenyl- 2-propinyl) -fi-chloropropionamide,

N( 3 -4-hydroxyphenyl-Z-propinyl -B-chl0ropropi onamide,

N- 3 -2-methyl amino phenyl-Z-p ropinyl 8- chloropropionamide,

N- 3 -4-dimethylaminoph enyl-2-propinyl -ft-chloropionamide,

N( 3 -2,6-dichl-orophenyl-Z-propinyl)-[3-ch1oropropionamide,

N- 3-4-methylthiophenyl-2-propinyl) -/3-chloropropionamide,

N- 3 -2-sulfamylphenyl-Z-propinyl) 6- chloropropionamide,

N- 3-4-cyclohexylphenyl-Z propinyl 3-ch1oropropionamide,

N- 3-4-cyclohexyloxyphenyl-Z-propinyl -fi-chloropr.opi-

onamide,

N( 3 -4-nitrophenyl-Z-propinyl) -B-chloropropi0namide,

N- (3-2-aminophenyl-2-propinyl)-5-ch1oropropionamide,

N- 3 -2-iodo-4-rnethylphenyl-2-propinyl) -,B-chloropropionamide,

N- 3-4-isopropylphenyl-Z-propinyl -B-chl0ropropionamide,

N- 3-4-phenyLphenyl-2-propinyl) -p-chl0ropropionamide,

N- (3-3 -phen-oxyphenyl-2-propinyl fl-chloropropionamide,

N- 3-4benzylphenyl-Z-propinyl -,B-chloropropionamide,

N-(3-3-acetamidophenyl-Z-propinyl) [3-ch1oropropionamide,

N- 3 ,4-acetylphenyl-Z-propinyloxy -,8- chlorop ropionamide,

N( 3 -2-ethylsulfionylphenyl-2-propinyl -N-b enzyl- (3-chloropropionamide,

N- (3 -3 ,4-methylenedioxyphenyl-Z-propinyl) -N-phenyl- ,B-chlorobutyramide,

N( 3-4- fluorophenyl-2-propinyl -fi-chloropropionam-ide,

N( 3 -4-chlorob enzylphenyl-Z-butinyloxy) -N-benZy-l-flchloropropionamide,

N- 3-1-methyl-2-naphthylphenyl-Z-propinyl -B-chlor.opropionamide, 1

N- (3-2chloro-1-naphthylmethylphenyl-Z-propinyl) 13-chloroprop-ionamide, and

N-(3-phenethylphenyl-Z-propiny1-oxy)-fi-chloropropionamide.

8. EXAMPLE 6 Preparation ofN-prapargyl-fl-(4-phe-nyl-1,2,5,6-tetrahydropyridino)propionamide Amixture containing 0.05 mole of 4-phenyl-1,2,5,6 tetrahydropyridine,0.05 mole of N-propargyl-B-chloropropionamide, 0.06 mole oftriethylamine, and 30 m1. of dimethylformamide is stirred and heated at70 for 4 hours. The reaction mixture is poured into 300 ml. of watercontaining 0.05 mole of sodium hydroxide. The product,N-propargyl-fi-(4-phenyl-1,2,5,6-tetrahydropyri- -dino)propionamide,separates as an oil which crystallizes upon standing.

EXAMPLE 7 Preparation ofN-propargyZ-B-(4-phenyl-1,2,5,6-tetrahydropyridino) propionamidehydrochloride The compound,Npropargyl-B-(4-pheny1-l,2,5,6-tetrahydropyridino)propionamide, preparedin Example 6, is dissolved in methylene chloride and converted to itshydroohloride salt by passing gaseous hydrogen chloride into thesolution. TheN-propargyl-B-(4-phenyl-l,2,5,6-tetrahydropyridino)propionamidehydrochloride precipitates out, and is recrystallized from n-butanol,and has a melt ing point of 107-110" C.

EXAMPLE 8 Preparation of Npropargyl0xy-B-(4-phenyl-1,2,5,6-tetrahydropyridino)prop io namide fumarate A mixture containing 0.05mole of 4-phenyl-1,2,5,6- tetrahydropyridine, 0.05 mole ofN-propargyloxy-B- chloropro-pionamide, 0.06 mole of triethylarnine and30 ml. of dimethylf-orm'amide is stirred and heated at 70 C. for fourhours. The reaction mixture is poured into 300 ml. of Water containing0.05 mole of sodium hydroxide. The product,N-propargyl0xy-B-(4-phenyl-1,2,5,6-tetrahydropyridino)propi-onamideseparates and is reacted with an equivalent amount of fumaric acid toform N-propargyloxy 5 (4 .phenyl 1,2,5,6 tetrahydropyridino)-propionamide fumarate which crystallizes out and has a melting point of141-1425 C.

EXAMPLE 9 Preparation of N-benzyl-N propargyl-fi-(4-phenyl-1,2,5,6-tetrahydropyridino) propionamide maleate A mixture containing4-phenyl-1,2,5,6-tetrahydropynidine (-0.05 mole),N-benzyl-N-propargyl-B-chloropropionamide (0.05 mole), triethylamine(0.06 mole), and dimethylf-ormamide (30 ml.) is heated at 70 C. for fourhours. The reaction mixture is poured into Water (300 ml.) containingsodium hydroxide (0.05 mole), and the product,N-benzyl-N-propargyl-,B-(4-phenyl-1,2,5,6-tetrahydropyridino)propionamide,is separated as an oil. The product is then reacted With an equivalentamount of maleic acid to form N-benzyl-N-propargyl-fl-(4-phenyl-1,2,5,6-tetrahydropyridino)propionamide m'aleate which is found to havea melting point of 138l39 C., and the following analysis.

Analysis.-Calcd. for C28H3QN2O5: C, H, 6.37%; N, 5.90%. Found: C,70.97%; H, 6.29%; N, 5.91%.

EXAMPLE 10 When equivalent quantities of the appropriate startingmaterials are substituted in the above procedures, the followingcompounds are obtained:

N-2-propinyl-,B- (4-phenyl-1,2,5,6-tetrahydropyridino)- butyramide,

N-2-propinyl- -(4-phenyl-1,2,5,6-tetrahydropyridino) butyramide,

N-2-butinyloxy-B-(4-phenyl-1,2,5,6-tetrahydropyridino)- propionamide,

'N-2-pro-pinyloxy-B- (4-phenyll ,2,5,6-tetrahydr-opyridino 'butyrarnide,

1 l N-2-propinyl-[3- [4- (4-ethylsulfonyphenyl -l ,2,5,6-

tetrahydropyridino] propionamide.

What is claimed is: 1. A compound selected from the group consisting ofcompounds of the formula wherein R and R are each a member selected fromthe group consisting of hydrogen, chloro, bromo, iodo, fluoro,trifluoromethyl, amino, nitro, (lower)alkyl, (lower) alkoxy, hydroxy,phenyl, phenoxy, benzyl, (lower) alkylamino, di(lower)alkylamino,(lower)alkanoylamino, (lower)alkylthio, sulfamyl, (lower)alkanoyl,(lower)alkylsulfonyl, methylenedioxy, cycloalkyl radicals having from 5to 7 carbon atoms inclusive and cycloalkoxy radicals having from 5 to 7carbon atoms inclusive,

W is a member selected from the group consisting of oxy(lower)alkyleneand (lower)alkylene,

Y is a (lower)alkylene radical,

Z and Z are each a member selected from the group consisting ofhydrogen, (lower)alkyl, pyridyl, thienyl and radicals of the formulae nis a whole integer from to 6 inclusive, and R and R are each a memberselected from the group consisting of hydrogen, chloro, bromo, iodo,fluoro, trifluoromethyl, amino, nitro, (lower) alkyl, (lower)- alkoxy,hydroxy, phenyl, phenoxy, benzyl, (lower)- alkylamino,di(lower)alkylamino, (lower)alkanoylamino, (lower) alkylthio, sulfamyl,(lower)alkanoyl, (lower)alkylsulfonyl, methylenedioxy, cycloalkylradicals having from to 7 carbon atoms inclusive and cycloalkoxyradicals having from 5 to 7 carbon atoms inclusive; and thepharmaceutically acceptable nontoxic salts thereof. 2. A compoundselected from the group consisting of compounds of the formula iZ-( JlIWCECH wherein R and R are each a member selected from the groupconsisting of hydrogen, chloro, bromo, iodo, fluoro,

trifluoromethyl, amino, nitro, (lower)alkyl, (lower)- alkoxy, hydroxy,phenyl, phenoxy, benzyl, (lower)- alkylamino, di(lower) alkylamino,(lower) alkanoylamino, (lower)alkylthio, sulfamyl, (lower)alkanoyl,(lower)alkylsulfonyl, methylenedioxy, cycloalkyl radicals having from 5to 7 carbon atoms inclusive and cycloalkoxy radicals having from 5 to 7carbon atoms inclusive,

W is a member selected from the group consisting of oxy(lower) alkyleneand (lower) alkylene,

Y is a (lower) alkylene radical,

Z is a member selected from the group consisting of hydrogen,(lower)alkyl, pyridyl, thienyl and radicals of the formulae and whereinR and R are each a member selected from the group consisting ofhydrogen, chloro, bromo, iodo, fluoro, trifluoromethyl, amino, nitro,(lower)alkyl, (lower) alkoxy, hydroxy, phenol, phenoxy, benzyl, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkylthio,sulfamyl, (lower)alkanoyl, (lower)alkylsulfonyl, methylenedioxy,cycloalkyl radicals having from 5 to 7 carbon atoms inclusive andcycloalkoxy radicals having from 5 to 7 carbon atoms inclusive,

W is a member selected from the group consisting of oxy(lower)alkyleneand (lower)alkylene,

Y is a (lower)alkylene radical;

and the pharmaceutically acceptable nontoxic salts thereof.

, compound selected from the group Consisting of compounds of theformula wherein R and R are each a member selected from the group W is amember selected from the group consisting of oxy(lower)alkylene and(lower)alkylene,

Y is a (lower)alkylene radical;

and the pharmaceutically acceptable nontoxic salts there- 5. A compoundselected from the group consisting of compounds of the formula wherein Wis a member selected from the group consisting of oxy(lower)a1kylene and(lower)alkylene, and

Y is a (lower)alkylene radical;

and the pharmaceutically acceptable nontoxic salts there- 6. A compoundselected from the group consisting of compounds of the formula wherein Wis a member selected from the group consisting of oxy(lower)alkylene and(lower)alkylene, and

Y is a (lower)alkylene radical;

and the pharmaceutically acceptable nontoxic salts there- 7. A compoundof the formula N HzCH2&-NHCH:;CECH

it. A compound of the formula 9. A compound of the formula 10. Acompound of the formula 11. A compound of the formula 12. A compoundselected from the group consisting of compounds of the formula 0 Z1A-Y-r i-l r-w-ozoz wherein A is a radical selected from the groupconsisting of chloro, bromo, iodo and tosyl,

W is a member selected from the group consisting of oxy(lower) alkyleneand (lower) alkylene,

Y is a (lower)alkylene radical,

Z and Z are each a member selected from the group consisting ofhydrogen, (lower)alkyl, pyridyl, thienyl and radicals of the formulaeQ-(mnmand (0 nHZn) wherein n is a whole integer from 0 to 6 inclusive,and R and R are each a member selected from the group consisting ofhydrogen, chloro, bromo, iodo, fluoro,

trifiuoromethyl, amino, nitro, (lower)a1ky1, (lower)- alkoxy, hydroxy,phenyl, phenoxy, benzyl, (lower)- alkylamino, di(lower)alkylamino,(lower)alkan0y1- amino, (lower)alkylthio, sulfamyl, (10Wer)alkanoyl,

5 (lower)alkysulfonyl, methylenedioxy, cycloalkyl radicals having from 5to 7 carbon atoms inclusive and cycloalkoxy radicals having from 5' to 7carbon atoms inclusive;

and the pharmaceutically acceptable nontoxic salts thereof.

WALTER A. MODANCE, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA